JPS58219196A - Production of 4'-demethyl-epipodophyllotoxin-beta-d- ethylideneglucoside - Google Patents

Abstract

PURPOSE:A specific demethyl-epipodophyllotoxin-ethylidene glucoside is subjected to alcoholysis to eliminate the acyl group, then to reduction to eliminate halogenoethoxycarbonyl to permit safe and high-yield production of the titled compound which is used as a carcinostatic agent. CONSTITUTION:The alcoholysis of 4'-halogenoethoxycarbonyl-4'-demethyl-epipodophyllotoxin-beta-D-2,3-di -0-acyl-4,6-ethylidene glucoside of formula I (Ac is acyl; me is methyl; X is halogen; m is integer of 0-2; n is integer of 1-3; m+n=3) is effected using methanol and anhydrous zinc acetate to eliminate acyls and the electrolytic reduction of the product removes halogenoethoxycarbonyl to give the objective compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4'-halogenoethoxycarbonyl-4'-demethyl-epipodophyllotoxin-β-D-2-3-
Di-0-acyl-4,6-etheridene glucoside (T)
4, characterized in that the acyl group is removed by alcoholysis, and the halogen ethoxycarbonyl group is removed by reduction.
The present invention relates to a method for producing '-demethylepipodophyllotoxin-β-ri-etheridene glucoside (It).

[In the formula, Ac represents an acyl group, ms represents a methyl group, X represents a halogen, m is an integer of O-2, n is an integer of 1-3, and m + n = 3] The above formula ( The compound represented by D is a new substance derived from the plant component podophyllotoxin having antitumor activity, and is also a compound represented by the above formula (U).
The compound represented by is called vP-16, has antitumor activity, and is a useful substance as an anticancer agent.

The following process is already known as a method for producing compound (U). (Refer to Japanese Patent Publication No. 46-3'i'83'7) In the c formula, R is polmyl or acetyl, mθ is the same as above,
φ represents a phenyl group. ) When removing the carbobenzoxy group, Nakayuko's method uses palladium-charcoal as a catalyst, which makes it difficult to complete the reaction when a large amount is synthesized, and may cause ignition when removing the catalyst. Therefore, the present inventors have conducted various studies on methods for producing compound (n) that do not have the above drawbacks, and have found that the compound (n) shown by formula (I) has disadvantages such as the risk of We have discovered that the compound (...) can be produced easily, safely, and with good yield even in the case of large-scale synthesis by using the compound (...) as a raw material.

The present invention was completed based on the above findings.

In the present invention, examples of the acyl groups at the 2- and 3-positions include an acetyl group and a formyl group.

Further, as the halogenoethoxycarbonyl group at the 4'-position, one having 1 to 3 chlorine, bromine, or iodine at the β-position is preferable, such as a β-iodoethoxycarbonyl group, a β-dichloroethoxycarbonyl group, β, β, β−
Examples include trichloroethoxycarbonyl group, β, β, β-tribromoethoxycarbonyl group, etc.
A β,β-trichloroethoxycarbonyl group is preferred.

Alcoholysis and reduction in the present invention can be performed in any order or both at the same time.

Alcoholysis is carried out in the presence of anhydrous zinc acetate in an alcohol such as methanol, ethanol, or a mixed solvent of these and dioxane, tetrahydrofuran, etc.
- This is carried out by heating under reflux for 30 hours.

The reduction is carried out, for example, by an electrolytic reduction method or by a method using a zinc-based catalyst. Examples of zinc-based catalysts include zinc powder, zinc-copper, zinc-silver, and zinc-mercury. It is sufficient to use the compound (1) in an amount of about 50-100 W/W%. In addition, acetic acid, methanol, and ethanol are used as the solvent, and water, dioxane, tetrahydrofuran, etc. may be used as an auxiliary solvent depending on the case. The reaction temperature is not particularly limited, but in the case of acetic acid it is carried out at 0°C to room temperature, and in the case of alcohol it is carried out at reflux temperature. The time required for the reaction varies depending on the solvent and temperature used, but is from 15 minutes to 2 hours.

In addition, when carrying out alcoholysis and reduction at the same time,
For example, compound (1) is mixed in an alcohol such as methanol or a mixed solvent of these with dioxane or tetrahydrofuran in the presence of zinc dust and anhydrous zinc acetate for 20 to 30%
It may be heated under reflux for a period of time.

Formula (1) used as a starting material in the present invention 4
It is synthesized using, for example, the following reaction route using '-demeter-evivodophyllotoxin (IV) (see Japanese Patent Publication No. 43-6 '469) as a raw material.

(V) □ (1) [In the formula, AC and mθ are the same as above] That is, 4'-demethyl-epipodophyllotoxin (IV
) with β,β2β-trichloroethoxycarbonyl chloride in an inert solvent.

β-Trichloroethoxycarbonyl-4'-demeter-epibodophyllotoxin (V) in the presence of boron trifluoride ethyl etherate in an inert organic solvent at a temperature below 0°C. (1) was synthesized by condensation of ethylidene-2,3-di-0-acyl-β-Dfrucohylanost.

The present invention will be specifically explained below with reference to Examples and Reference Examples.

Example 1 Method for producing 4'-demeter-evivodophyllotoxin-β-D-ethylidene glucoside 4'-β,β,β-trichloroethoxycarbonyl-4
'-demethyl-epipodophyllotoxy/-β-ri12,
A solution of 3-di0-7 cetyl-4.6-ethylidene glucoside (100wq), zinc dust (looq) and anhydrous zinc acetate (15wg) in methanol (4d) was
Heat to reflux for 2 hours. After the reaction was completed, chloroform ('15
Ile) and filter to remove zinc dust. The chloroform layer is washed with water (2a/x2) and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (effluent solvent: chloroform: methanol = 20:l). Yield 40 capes (yield 57%) m, p, 24B - 252°C Rf+ = 0.21 (chloroform: methanol - 20 + 1) Example 2 a) 4'-demeter-evibodophyllotoxin-β ~ D
-2. Process for producing 3-di-0-acetel-4,6-ethylidene glucoside (U) Elimination of β, β, β-trichloroethoxy carbonyl group using zinc dust-acetic acid 4'-β, β, β-trichloroethoxy carbonyl-4
'-demeter-evivodophyllotoxin-β-D-2,
3-di-O-acetel-4,6-ethylidene glucoside (200 tries) was mixed with acetic acid-dioxin (4 mL:1
), add zinc dust (200η) to the solution, and stir at room temperature for 1 hour. After the reaction is complete, ethyl acetate (15R
Add t) and filter. The ethyl acetate layer was diluted with water (5 ml
Wash with 2) and dry with anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and a small amount of methanol is added to the resulting oily substance, which crystallizes. Yield 14c1wI0 (Yield 8B
%) (2) β, β, β using zinc dust-methanol
-Elimination of trichloroethoxycarbonyl group, 4'-β,β,β-trichloroethoxycarbonyl group
'-demeter-evivodophyllotoxin-β-D-2,
3-G〇-acetyl-4.6-etheliding. After the reaction is completed, ethyl acetate (lamg) is added and filtered to remove zinc dust. The ethyl acetate layer was washed with water (3 ml x 2) and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and a small amount of methanol is added to the resulting oily substance, which crystallizes. Yield 57Tng (yield 72%) This compound is the compound obtained in (1) and m-p, +
1. R1°N, M, and R all matched.

b) Process for producing 4'-demethyl-epipodophyllotoxin-β-ethylidene glucoside 4'-demeter-epipodophyllotoxin-β-D? obtained in a) above? -2,3-G〇-acetyl-4,6
- methanol-tetrahydrofuran (5 m
The solution of l 4'+1) is heated to reflux for 22 hours. After the reaction is complete, chloroform (20 alV) is added. The organic layer was washed with water (3mex2) and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent solvent: 2 chloroform: methanol e-20: l). Yield: 49η (yield: 71cm) Reference example 4'-β,β,β-trichloroethoxycarbonyl-4
'-demeter-evivodophyllotoxin-β-D-2,
Process for producing 3-di-O-acetyl-4,6-ethelidene glucoside (a) Process for producing 4'-β,β,β-trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin 4'-demethyl-epipodyl Dophyllotoxin (2f) was suspended in anhydrous ethylene chloride (3smt), then anhydrous pyridine (440 ml) was added and cooled to -20°C. A solution of β, β, β-trichloroethoxycarbonyl chloride (1,17F) in anhydrous ethylene chloride (3Rt) was added dropwise to this solution over a period of 30 minutes, and the reaction was stirred for an additional 30 minutes. After the reaction is completed, the reaction solution is washed with water (20mex2) and the organic layer is dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the resulting crude product was mixed with acetone/
Recrystallize from ether. Yield 2. a4f (yield 92cm).

For further fPIg, recrystallize from methanol.

m, p, 1, R,')) Nujol 3540, 3425. with dual melting points of 141-142°C and 219-220°C.
ll7s5゜aX 1'/60,16□. cm-1 N, M, R (CDCl3) J 3-'73 (64
B) OCH2X 2 (tit 4'-β, β,
Preparation of β-trichloroethoxycarbonyl-41-demeter-evibodophyllotoxy 7-β-D-2,3-di-0-acetyl-4,6-ethylidene glucoside 4'-β,β,β-trichloroethoxycarbonyl -4
'-Demethyl-epipodophyllotoxin (5'i'5.
4) Dissolve it in anhydrous ethylene chloride (4me) by heating, then cool the solution to 20°C, and while stirring, 4.
6-0-ethylidene-2,3-di-0-ace, thiru β
-D-,/Lucopyranose (320q) was added and stirred at 20°C until the sugar component was dissolved.

Once dissolved, the reaction solution was immediately cooled to -20°C and boron trifluoride etherate (0-3,5at, 48% BF3)
was added dropwise, and then stirred at -20°C for 40 minutes.

A solution of anhydrous pyridine (0,35,tttl) in ethylene chloride (1, ml) is stirred and cooled. Ethylene chloride (104g) was added to the reaction solution, and water (lodx
3) Wash the organic layer with anhydrous sulfuric acid and dry with IJum.

After drying, the solvent is distilled off under reduced pressure and the resulting viscous substance is purified by silica gel chromatography (eluent: toluene:ethyl acetate - 4:1) to obtain the desired product as a white foam. Yield: 790 cm (Yield: 93 cm) For further purification, recrystallization from methanol is performed.

m, p, 166-168℃ 2.05 (3H, S) O-CCH Nrin-3, '70 (6H, S) -ocn3x2 Patent applicant Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] 1. Formula [In the formula, Ac represents an acyl group, mθ represents a methyl group, and X...
Indicates rogen, m is 0-2! 4'-halogenoethoxycarbonyl-4'-demethyl-
A formula characterized in that the acyl group of epipodophyllotoxin-β-D-2-3-di-0-acyl-ichiban-6-nitylidene glucoside is removed by alcoholysis and the halogenoethoxycarbonyl group is removed by reduction [ A method for producing 4'-demethylepipodophyllotoxin-β-ri-etheridene glucoside represented by the formula, mθ is the same as above.